Judicious Use of Anticoagulation: A Case-Based Approach

Michael B. Streiff, MD, FACPAssociate Professor of Medicine and Pathology

Division of HematologyMedical Director, Johns Hopkins Anticoagulation

Management Service and Outpatient Clinics

Disclosures

• Research Funding– Bristol-Myers Squibb– NIH/NHLBI

• Consulting– Sanofi-aventis– Eisai, Inc. – Daiichi-Sankyo– Janssen Healthcare– BiO2

• Speaking Honoraria– Sanofi-aventis– Ortho-McNeil

• Educational Grants– Sanofi-Aventis– Covidien

Anticoagulation for pregnancy loss

• 32 year old woman with 2 previous first trimester pregnancy losses asks about LMWH to prevent miscarriages. You advise her to – Start therapeutic dose LMWH– Start prophylactic dose LMWH– Start prophylactic dose LMWH + Aspirin 100 mg– Start no antenatal prophylaxis

LMWH does not improve pregnancy outcomes: The ALIFE Study

Placebo (N=121)

Aspirin 80 mg (N=120)

Aspirin 80 mg + Nadroparin 2850 IU(N=123)

Completed Study (N=103)

Completed Study (N=97)

Completed Study (N=99)

364 women with at least 2pregnancylosses

Kaandorp S et al. NEJM 2010

Baseline characteristics

Characteristic Aspirin + LMWH (N=123)

Aspirin (N=120)

Placebo (N=121)

Age (yrs.) 34±5 33±5 34±5

Previous miscarriages

3 (2-15) 3 (2-9) 3 (2-12)

≥ 3 miscarriages 73 (59%) 71 (59%) 74 (61%)

≥ 1 late losses 40 (33%) 38 (32%) 35 (29%)

Previous live birth 53 (43%) 45 (38%) 46 (38%)

Thrombophilia 13 (12%) 17 (17%) 17 (17%)

Kaandorp S et al. NEJM 2010

LMWH did not increase the live birth rate

Kaandorp S et al. NEJM 2010

Thrombophilia did not affect live birth rate

Nadroparin + ASA

ASA Placebo0

10

20

30

40

50

60

70

8069.2

64.7

52.948.9

58.5 58

ThrombophiliaNo Thrombophilia

Live

Birt

h Ra

te (%

)

Kaandorp SP et al. NEJM 2010

Anticoagulation does not prevent early pregnancy loss

• Open-label RCT of enox 40 mg/d + ASA 75 mg vs. surveillance alone

• PMHx ≥ 2 losses 24 weeks or less

• Begin 7 weeks gestation or less

• Conclusion- Prophylactic AC does not improve pregnancy outcomes

Pregnancy loss Bleeding0

5

10

15

20

25

20

15.6

22

16

Surveillance aloneEnox 40 + ASA

Adve

rse

Even

ts (%

)

N=294

Clark P et al. Blood 2010

Heparin + Aspirin reduces pregnancy loss in Antiphospholipid Syndrome

• Metanalysis of 5 RCTs of UFH/LMWH + aspirin versus aspirin

• Regimens- UFH 5000-20000 units + aspirin 75-81 mg and LMWH 5000 + aspirin 75-81 mg

• Conclusion- UFH/LMWH + ASA improves live birth rates Live Birth

0

10

20

30

40

50

60

70

80

55.8

74.3

Aspirin (N=163)UFH/LMWH + ASA (N=171)

Live

Birt

hs (%

)

Mak A et al. Rheumatol 2010

RR 1.3

Anticoagulation- Less or More?

• A 65 year old man with a St Jude aortic valve is scheduled to undergo a prostatectomy for cancer. When should he resume full-dose anticoagulation?– 12 hours post-op– 24 hours post-op– 36 hours post-op– 72 hours post-op

Perioperative AC- Is less more?

• Metanalysis of 34 studies of 12,278 patients

• Outcomes- Thromboembolism and Bleeding

• Limitation- Lack of RCT• Conclusion- Value of

perioperative bridging unclear Bleeding Thrombosis

0

2

4

6

8

10

12

14

1613.6

0.4

8.5

0.2

3.4

0.6

Full Dose Prophy DoseNo Bridge

Patie

nts (

%)

Siegal D et al. Circulation 2012

Less is more for perioperative AC

• Prospective Cohort of 1262 patients

• Low risk- AVR w/o Afib-prophylactic LMWH

• High risk- MVR, AVR w/Afib or stroke- Enox 0.7 mg/kg q12h

• Post-op- resume AC day 1-3 based upon hemostasis Thrombosis Major Bleed

0

0.5

1

1.5

2

2.5

3

1.7

2.7

0

0.700000000000001

High TE risk Low TE risk

Pengo V et al. Circulation 2009

Thromboembolism Risk Stratification Thromboembolic Risk

Atrial Fibrillation Mechanical Valve Venous Thromboembolism

High CHADS2 score 5 or 6 Any Mitral valveOlder valve (Caged-ball, Tilting disk)Recent stroke/TIA

Recent (within 3 mos.) VTESevere thrombophilia

Intermediate CHADS2 score 3 or 4 Bileaflet Aortic valve + TE risk factors

VTE within 3-12 mos.Recurrent VTE, Active CancerNon-severe thrombophilia

Low CHADS2 score 0-2 Bileaflet Aortic valve w/o TE risk factors

VTE > 12 mos.

TE risk factors= A fib, Cardiac failure, HTN, DM, Age > 75, Stroke/TIADouketis JD Blood 2011

Bleeding Risk Assessment Low Bleeding Risk Procedures High Bleeding Risk Procedures

CholecystectomyAbdominal hysterectomyGI Endoscopy ± biopsy or stentPacemaker insertion, EP testingDental extractionsCarpal tunnel repairDilatation/currettageSkin Cancer excisionAbdominal herniaHydrocele repairCataract surgeryBronchoscopy ± biopsy Central Venous Catheter removalSkin, Thyroid, Breast, Lymph node biopsy

Cardiac surgeryAbdominal aneurysm repairNeurosurgeryUrologic surgeryHead and Neck surgeryHip/knee replacementBack surgeryKidney biopsyPolypectomy/sphincterotomyTransurethral prostate resection General surgeryVascular surgeryAny major surgery (> 45 minutes)

Spyropoulos AC and Douketis JD Blood 2012

AC Management

Surgical Bleeding risk Pre-operation Post-operation

Low Last dose LMWH 24 hours before

Resume LMWH 24 hours post-op if hemostasis adequateStart warfarin with LMWH

High Last dose LMWH 24 hours before

Resume LMWH 48-72 hours post-op if hemostasis adequate or start prophylactic dose 24 hours post-op or avoid LMWHStart warfarin with LMWH

Anticoagulation for VTE• 65 year old man develops a right femoral-

popliteal vein DVT 1 week after right knee replacement. A thrombophilia evaluation reveals he is heterozygous for the factor V Leiden mutation. How long should he be treated?– 6 weeks– 3 months– 12 months– Indefinite

Anticoagulation for VTE

• 48 year old man presents with progressive dyspnea over 1 week and left leg discomfort. CT angiogram identifies bilateral PE. Duplex study finds a left leg DVT. No VTE risk factors are identified. How long should he be treated?– 3 months– 6 months– 12 months– Indefinite

Do the Results of Thrombophilia Tests Help to Determine Duration of Therapy?

Baglin, 2003 Christiansen, 2005 Santamaria 2005 Prandoni 200705

1015202530354045

Thrombophilia No thrombophilia

HR 1.5 (0.8-2.8)

(N= 570)24 mos.

(N=474)84 mos.

(N=267)46 mos.

(N=1626)50 mos.

HR 1.4 (0.9-2.2)

HR 1.8 (1-3.1)

HR 2.0 (1.5-2.7)

Rec

urre

nt V

TE (%

)

Thrombophilia-Assessing the risk

• High risk thrombophilia– Antithrombin deficiency - 1.8 % per year (95% CI 1.1-2.6%)– Protein C deficiency - 1.5% per year (1.1-2.1%)– Protein S deficiency - 1.9% per year (1.3-2.6%)

• Moderate risk thrombophilia– Factor V Leiden - 0.5% per year (0.4-0.6%)– Prothrombin gene mutation - 0.3% per year (0.2-0.5%)– Factor VIII - 0.5% per year (0.4-0.5%)

• Low risk thrombophilia– Factor IX - 0.1% per year (0.02-0.2%)– Factor XI - 0.2% per year (0.06-0.6%)– Hyperhomocysteinemia – 0.1% per year (0.05-0.3%)

Lijfering WM et al. Blood 2009

Antiphospholipid syndrome is associated with recurrent thromboembolism

0 6 12 18 24 30 36 42 480

5

10

15

20

25

30

35

ACL - ACL +

Rec

urre

nt V

TE (%

)

Months

Schulman S , et al. Am J Med 1998; 104: 332-338

P=0.0013

VTE recurrence rate varies depending upon initial trigger for the event

0 4 8 12 16 20 240

5

10

15

20

25

Recent surgery Non-surgical risk factor Idiopathic

Time after cessation of therapy (months)

Cum

ulat

ive

recu

rren

t VTE

(%)

Baglin T et al., Lancet 2003

N = 570

VTE Setting influences recurrence risk

• Systematic review of prospective cohort studies and RCTs

• 15 Studies• 5159 Subjects• Follow up- 3-96 months• Conclusion- Setting of

thrombosis strongly influences recurrence rate

Surgi

cal tri

gger

Non-surgi

cal tri

gger

Idiopathic

012345678

0.700000000000001

4.2

7.4

Recu

rren

t VTE

(% p

er p

at.-y

r)

Iorio A et al. Arch Intern Med 2010

D dimer and recurrent VTE• D dimer- an indirect marker

of activated coagulation• PROLONG study (Palareti G et al.

NEJM 2006)

– F/U 1.4 years• Systematic Review (Verhovsek M

et al. Ann Intern Med 2008)

– 7 studies, 1888 patients– Recurrent VTE- Abnl vs.

nl DD (8.9% vs. 3.5% per year)

N=608

How do we identify the low risk patient with idiopathic VTE?

• Prospective cohort study of 665 patients with idiopathic VTE– Enrolled at 12 centers, 4 countries prior to DC of warfarin after 5-7

months of therapy– Information of 76 laboratory and clinical variables associated with VTE

were collected– Multivariate analysis used to develop clinical prediction rule for

recurrent VTE• Results

– F/U population 600/665 (90%)– Mean F/U -18 months (1-47 mos.)– Annual risk of recurrent VTE 9.3% per year (7.7%-11.3%)

• Men 13.7% (10.8%-17%)• Women 5.5% (3.7%-7.8%)

Rodger MA, et al. CMAJ 2008;179(5):417-26

Clinical prediction rule for recurrent VTE in women

Rodger MA, et al. CMAJ 2008;179(5):417-26

Risk stratification for idiopathic VTE: The Vienna Risk Model

Eichinger S et al. Circulation 2010

0 12 24 36 48 60 72 84 96108

12005

10152025303540

Months after discontinuation of anticoagu-lation

VTE

(%)

http://www.meduniwien.ac.at/user/georg.heinze/zipfile/ViennaPredictionModel.html

Indefinite Anticoagulation: Weighing the risks

Thrombosis Bleeding

Assessing Bleeding Risk: The HAS-BLED Score

• HASBLED– Hypertension (uncontrolled

SBP>160) = 1 point– Abnormal renal/liver function

= 1 or 2 points– Stroke = 1 point– Bleeding (or anemia) = 1

point– Labile INRs (TTR<60%)= 1

point– Elderly (Age > 65 years)= 1

point– Drugs or alcohol= 1 or 2

points

Low (0

-1 pt.)

Intermediat

e (2-3 pts.

)

High (4

+)0123456789

2.66

5.54

8.11

Maj

or B

leed

(per

100

pt.-

yrs.

)

N=44,771

Pisters R et al. Chest 2010; Olesen JB, et al. JTH 2011

Central Venous Catheter Prophylaxis

• 67 year old man has just had a right subclavian Hickman CVC placed for chemotherapy for recently diagnosed NHL. What should be used for CVC thrombosis prophylaxis?– Warfarin 1 mg daily– Enoxaparin 40 mg daily– Dalteparin 5000 units daily– No prophylaxis necessary

CVC Prophylaxis

• Open RCT of low dose warfarin 1 mg vs. no warfarin

• Start 3 days before CVC insertion

• Outcome-Venogram with symptoms or at 90 days

• Conclusion- Low dose warfarin prevents CVC thrombosis

0 10 20 30 40 50 60 70 80 900

5

10

15

20

25

30

35

40

Warfarin No Warfarin

Days

Veno

us T

hrom

bosi

s (%

)

Bern MM et al. Ann Intern Med 1990

P<0.001

Catheter ProphylaxisStudy Regimen Outcome

assessmentDVT (%) P Value

Bern et al. 1990

Warfarin 1 mgNo treatment

Venogram 9.537.5

<0.001

Monreal et al. 1996

Dalteparin 2500 No treatment

Venogram 662

0.002

Reichardt et al. 2002

Dalteparin 5000No treatment

Clinical 3.73.4

0.9

Couban et al. 2003

Warfarin 1 mgPlacebo

Clinical 4.64

0.81

Verso et al. 2004

Enoxaparin 40 mgPlacebo

Venogram 14.118

0.35

0 1 2 3 4 5 6 7 8 9 1011120

2

4

6

8

10

12

14

16Fixed-dose Dose-adjusted

Time from randomization (mos.)

Thro

mbo

sis (

%)

P=0.002

Young AM, et al. Lancet 2009

• A multicenter (N=68) open label study of warfarin CVC prophylaxis (N=1590)

• Study Arms-– No warfarin (404) vs. warfarin

1 mg (408)– Warfarin 1 mg (471) vs.

warfarin (INR1.5-2.0) ( 473)• Conclusion- Dose-adjusted

warfarin is required to prevent CVC DVT

Adjusted dose warfarin prevents CVC thrombosis: WARP study

Elevated INR- Less vitamin K is more

• 70 year old man taking warfarin for atrial fibrillation has an INR of 7. He does not have any signs of bleeding. What should you do?– Hold warfarin and administer vitamin K 2.5 mg po– Hold warfarin and administer vitamin K 2.5 mg IV– Hold warfarin and recheck INR in 1-2 days– Hold warfarin and administer Vitamin K 2.5 mg

and 3 units of FFP

Less vitamin K is more safe• RCT of vitamin K 1.25 mg or

placebo for pts. with INR 4.5-10

• Setting- 14 AC clinics in US, Canada, Italy

• Outcomes- Symptomatic bleeding or thromboembolism within 90 days

• Conclusion- Oral Vit K does not improve outcomes with INR 4.5-10

Bleeding Major Bleed

TE Death02468

1012141618 16.3

1.1

41.9

15.8

2.5 32

Placebo (N=369)Vitamin K 1.25mg (N=355)

Crowther MA et al. Ann Intern Med 2009

Is less is more?• 72 year old man with atrial fibrillation who has been on

warfarin 5 mg daily for 3 months. Today his INR is 1.8. No reason identified. What should you do with his warfarin dose?– Increase his dose to 7.5 mg MWF, 5 mg ROW (21% dose

increase), recheck 1 week– Increase his dose to 7.5 mg daily (50% dose increase),

recheck 1 week– Increase his dose to 7.5 mg W, 5 mg ROW (7% dose

increase, recheck 1 week– Continue same dose, recheck 1 week

Less dose adjustment=more time in range

• Observational study of warfarin management

• Setting- 94 AC clinics, 3961 patients

• Outcome- Time in therapeutic range

• Conclusion- Excessive warfarin dose changes lead to poorer INR control

INR 2-3 INR 1.9-3.1

INR 1.8-3.2

INR 1.7-3.3

62

64

66

68

70

72

74

76

67

69

74

71

INR Target Range

Tim

e in

ther

apeu

tic ra

nge

(%)

Rose AJ et al. J Thromb Haemost 2009

Is less LMWH more?

• A 65 year old man with an atrial fibrillation (CHADS2 score 3) who has been on warfarin for 4 months has an INR of 1.5. Your nurse asks you for advice. You suggest…– LMWH + warfarin dose increase– Warfarin dose increase only

Less LMWH is safe• Retrospective study of

patients in Kaiser CO AC clinics

• Low INR and therapeutic INR groups

• Only 13 patients received LMWH

• Outcomes- Bleeding and TE at 90 days

• Conclusion- LMWH not necessary for most patients with low INR

Thrombosis

Bleeding Death0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

0.4

1.5

0.20.1

0.8

0.2

Low INR (N=1080)Therapeutic INR (N=1517)

Patie

nts (

%)

Clark NP et al. Pharmacother 2008

Conclusions• Anticoagulation is not indicated for recurrent early pregnancy

loss except perhaps APS• Therapeutic AC should be used sparingly in the post-operative

period• Setting rather than presence of thrombophilia dictates

duration of therapy• Risk stratification models can help determine the risk of

recurrent VTE and bleeding in patients with idiopathic VTE• Central venous catheter prophylaxis remains of unproven

benefit• Studies continue to optimize warfarin management

Questions ?